Liposomes, also known as vesicles, are generally composed of phospholipids and other lipid components such as cholesterol. They can function as carriers whose essential structural feature is a bipolar lipid membrane which envelops an aqueous core volume in which pharmacological agents are solubilized and therefore encapsulated. Liposomal encapsulated drugs have shown promise in treating diseases and have performed as diagnostic tools for the early detection of cancer and other maladies. As a result, liposomes have shown potential as site-specific carrier systems for a variety of therapeutic agents including enzymes for enzyme replacement therapy, hormones, cell modifying agents and genetic material. The pharmaceutical products which have been delivered to designated sites in vivo have demonstrated an improvement in therapeutic indices. Thus, by using liposomes for site-specific delivery, the results show a general lowering of adverse side effects as lower overall doses of therapeutic agents are administered. Agents that are delivered in a conventional or non-specific manner often spread or are dispersed to non-designated areas and thus exhibit adverse side effects and unwanted pharmacological responses.
Various lipid formulations and methods for their preparation have been described for the delivery of pharmaceutically active agents to a host.
Geho and Lau in U.S. Pat. No. 4,603,044 describe a targeted liposomal delivery system for delivery of a drug to the hepatobiliary receptors of the liver. The system is composed of a drug or diagnostic agent encapsulated in or associated with lipid membrane structures in the form of vesicles or liposomes, and a molecule having a fatty substituent attached to the vesicle wall and a target substituent which is a biliary attracted chemical, such as a substituted iminodiacetate complex.
Geho in U.S. Pat. No. 4,761,287 describes the delivery of serotonin to the liver using a hepatocyte directed vesicle (HDV).
Geho and Lau in U.S. Pat. No. 4,863,896 disclose the delivery of encapsulated insulin in a hepatocyte directed vesicle in conjunction with a simultaneous supply of free insulin.
While there have been some advances in the art of targeted delivery systems, many of these systems have relied on the sequential addition of targeting moieties to the exterior surface of a liposomal membrane so that the carrier system can deliver the therapeutic to a designated site-of-action. The present invention is distinguishable from prior art systems in that particular target molecules, have been discovered that are not only hepatocyte specific, but can be incorporated into a liposomal carrier construct in a one-step addition procedure at the time of manufacture.
Accordingly, it is an object of this invention to provide a water-insoluble structure, e.g., a chromium complex, as well as other water-insoluble amorphous complexes, that will dissolve in a liposomal lipid matrix and enable the liposomal construct, in conjunction with a therapeutic or diagnostic cargo, to be delivered to the hepatocytes in the liver of a warm-blooded host.
Further, it is an object of the invention to provide an amorphous water insoluble target molecule in a dissociated form which is a product of the interaction between the essential target molecule and the liposomal membrane which produces a dissociated species that present itself as a hepatocyte targetable derivative of the parent compound.
It is also an object of the invention to produce a chemical means for synthesizing the amorphous organic target complex from aqueous media.
A still further object of the invention is to incorporate a hepatocyte targeting molecule into the liposomal construct utilizing a single-step manufacturing process.
An even further object of the invention is to produce an injectable form of the hormone insulin which is convenient to formulate either during the manufacturing process or later by a registered pharmacist thus making it easy for a diabetic patient to administer the insulin by subcutaneous injection.
Still another object of the invention is to provide a hepatocyte directed liposomal delivery system for insulin replacement therapy that will provide a means for achieving better glucose homeostasis in the liver and plasma of a warm-blooded host.
These and other objects and features of the invention will be apparent from the following summary and description of the invention and from the claims.